DESCRIPTION: NBCR will develop new computational technologies to create stronger, clearer connections across diverse scales of biological organization ~ from molecules to whole-organ systems. We will develop new modeling paradigms, tools, technologies, and corresponding expertise to bring the crossing of scales into routine practice, leveraging a new era in biomedical science already enriched by a wide variety of types, sizes, and sources of data. To achieve these goals, we plan to pursue activities in four parallel core project areas: To achieve these goals, we plan to pursue activities in four parallel core project areas: Core 1 will advance technologies for atomic-to-subcellular simulation and discovery to enable investigation of large-scale biological systems with unprecedented accuracy and transform current state-of- the-art computational capabilities approaching the mesoscale. Core 2 will focus on creating a flexible model assembly environment for cells and subcellular scenes, facilitating incorporation of data from multiple methods and the capability of connecting into various simulation engines, thus enabling crossing from molecular to cellular scales for individual cells and cells in tissues. Core 3 will expand its interactive and extensible multi-scale modeling environment connected with a publicly available database containing experimental data, models, and model components with improved methods to more tightly integrate coupling between physiological scales that range from the molecular (with Cores 1 and 2) to whole-organ. Core 4 will focus on practical cyber-infrastructure, which unites all the cores and the various requisite computing elements to provide a framework that enables routine and effective use of ubiquitous and increasingly diverse computational and data architectures. Our proposal describes a coordinated development plan among the four cores, in close collaboration with Driving Biomedical Project investigators, that will harness the data deluge to develop insights from detailed structural models, develop and probe computational multi-scale functional models, and create and disseminate robust, reusable workflows that will make seamless integration across scales routine practice in biomedical research.